Neuropathology Cores directed by Dr. DeArmond have been part of Stanley Prusiner PPGs for the past 25 years. The overall goal has been to test the hypothesis that emerged from Dr. DeArmond's early correlative kinefic studies of PrP [Sc] neurochemistry, PrP[Sc] immunohistochemistry, and neuropathological analysis during the course of prion diseases, which stated that formation and accumulation of PrP[Sc] in neurons are the cause ofthe clinically relevant neuropathological changes. All of our evidence today suggests that neurodegeneration in prion diseases progresses in stereotypical sequence of pathogenic events that underlies neurological dysfunction and degenerafion in prion disease. The sequence encompasses a progression of funcfional and neuropathological changes that begin with formafion and accumulafion abnormal protease resistant PrP*^ in neurons, proceeds rapidly to synaptic degeneration as PrP^^ accumulates in plasma membranes, and terminates in autophagic nerve cell death when PrP accumulates in lysosomes and autophagosomes. The main theme of this PPG's Projects is prion strains. Project 1 proposes to create multiple synthetic prions and compare their physical characteristics with their pathologic phenotype in transgenic mice. In Project 2, yeast prions Sc4 and Sc37 will be mutated to test their ability to infect mammalian cells in vitro and in vivo. Project 3 proposes to use induced neuronal cells (iN cells) carrying mutations in genes associated with neurodegenerafion, such as APP, presenilin-1 and tau, and test whether the gene mutations predispose them for prion-like infecfion. The Neuropathology Core has all techniques and expertise to analyze the fissues provided to us. The resulfing pathologies may be novel.